Many AIDS patients can now expect to live a long life because highly active antiretroviral therapies (HAART) effectively suppress HIV replication to undetectable levels. However, chemotherapy is associated with severe side effects that affect long-term health, is very expensive, and as such interferes with adherence by patients. Therefore, there is a continued need to develop and optimize therapy regimens to lessen side effects, promote better adherence, and increase the relative drug efficacy. The Baltimore and the Trkola laboratories have recently questioned the effectiveness of antiretroviral therapies and neutralizing antibodies during HIV cell-to-cell transmission. Cell-to-cell transmission allows efficient viral spreading via sites of cell-cell contact designated virological synapses. Importanty, it increases the number of proviruses in infected target cells thereby leading to higher viral gene expression as compared to infections by cell-free HIV. The higher effective local MOI leads to a high multiplicity of infection that can result in the increased resistance of cell-to-cell transmision to antiviral therapies. These recent observations require a re-evaluation of commonly used antiretroviral therapies against HIV cell-to-cell transmission. Here we propose to systematically test the effectiveness of numerous antiretroviral inhibitors against HIV cell-to-cell transmission. We hypothesize that the observed resistance to anti-retroviral drugs depends on the inhibitory potential of the drug. Drugs with high inhibitory potential may be the most effective against cell-to-cell transmission of HIV. We will apply a highly sensitive and quantitative assay that measures HIV cell- to-cell transmission as a necessary first step to re-evaluate the efficacy of commonly used antiretroviral inhibitors. Our experiments have the potential to further optimize existing HAART regimens.